Submitting an IND: What You Need to Know

Submitting an IND: What You Need to Know

Maria R. Walsh, RN, MSAssociate Director for Regulatory Affairs (Acting)Office of Drug Evaluation III,OND/CDER/FDA

SBA Educational Forum October 15, 2009

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Topics1. IND Application: Content and Format2. IND Submission: The First 30 Days3. Responsibilities of Sponsors and Investigators4. IND Amendments5. Reporting Requirements6. Inactivation; Reactivation; Withdrawal;

Termination


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IND Application: Content and Format

Content• Requirements outlined in 21 CFR 312.23

– Cover Letter– Form FDA 1571– Form FDA 3674– Table of Contents– Introductory Statement/General Investigational Plan– Investigator’s Brochure


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• Nonclinical– Sufficient data to support clinical protocol – Basic exposure data

• Chemistry, manufacturing, and controls– Sufficient information to assure proper identification,

quality, purity, and strength– Sufficient information to assess whether batches can

be adequately produced and consistently supplied


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• Clinical protocol– Determine the phase of development– Provide supporting data (e.g., from ex-U.S.

trials, PK data)– Specify how to ensure safety of the

subjects/patients in the study (#1 reason INDs are placed on clinical hold)


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• Bundling: One IND or More?

– One IND:• Early development studies - not sure of indication or dosage

form• Closely related indications within a single review division• Multiple, closely-related routes of administration using same

dosage formulation• Combination of two or more investigational new drugs for

concomitant use


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• Bundling: One IND or More?

– Multiple INDs:• Two or more unrelated conditions being developed• Multiple dosage forms being extensively investigated• Multiple routes of administration being extensively

investigated


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Format• Paper

– Common Technical Document (CTD) format – Regulatory format (21 CFR 312.23)

• Electronic – Must use CTD format– Physical media– Electronic Submissions Gateway (ESG)


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Mailing address:

Food and Drug AdministrationCenter for Drug Evaluation and Research

Central Document Room5901-B Ammendale RoadBeltsville, MD 20705-1266

No user fee required!


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IND Application: Resources

How Drugs are Developed and Approved:• http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDeve

lopedandApproved/default.htmIND Application (includes links to all IND guidances):• http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDeve

lopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplic ation/default.htm

Small Business Assistance: FAQs on Drug Development and INDs• http://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssi

stance/ucm069898.htmCTD Format Guidances:• http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guid

ances/ucm065006.htm

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/default.htm

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/default.htm

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/default.htm



http://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/ucm069898.htm

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/ucm069898.htm

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065006.htm

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065006.htm


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IND Application: Resources

Electronic Submissions:• http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmission

Requirements/ElectronicSubmissions/default.htm• Preparation questions: [email protected] Submissions Gateway:• http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/default.htm• Preparation/Registration/Policy Questions: [email protected]• Technical Issues: [email protected] e-mail account:• Contact Wendy Lee at: [email protected] application number:• Send one email per application number request to

[email protected].

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/default.htm

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/default.htm

mailto:[email protected]

http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/default.htm






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IND Submission: The First 30 Days

• IND arrives in the Central Document Room

– If electronic: Loaded into the EDR( Electronic Document Room)

– If paper: Sent to White Oak Document Room– Data entered into DARRTS (Document Archiving,

Reporting, and Regulatory Tracking System)– Review division’s Chief, Project Management Staff

(CPMS) notified


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• Regulatory Project Manager (RPM) assigned

– Your point of contact with the review division– Issues IND Acknowledgement letter (includes IND

number; receipt date; address for future submissions; contact information)

– Performs regulatory/administrative review of IND application for completeness

– Tracks/manages IND review process


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• Scientific Discipline Team Leaders notified and reviewers assigned

– Clinical– Nonclinical pharmacology/toxicology– Chemistry– Clinical pharmacology– Biostatistics (if phase 3 protocol)– Consult reviewers as needed


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• Safety Review

– The review division will determine within 30 days of receipt of your IND whether your study is “reasonably safe to proceed” (active) or will be placed on clinical hold

– Some review divisions may issue a “safe to proceed” letter; Otherwise, “No news is good news”

– INDs are not approved


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IND Submission: Clinical Hold

• Clinical Hold: [21 CFR 312.42(a)]

– An order issued by FDA to the sponsor of an IND to delay a proposed clinical investigation or suspend an ongoing clinical investigation

• Full Clinical Hold: A delay or suspension of all clinical study under an IND.

• Partial Clinical Hold: A delay or suspension of only part of the clinical study under an IND (e.g., a specific protocol or part of a protocol is allowed to proceed).


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• Grounds for imposing a clinical hold for phase I trials: [21 CFR 312.42(b)(1)]

– Human subjects would be exposed to an unreasonable and significant risk of illness or injury

– Clinical investigators are unqualified– Investigator Brochure is misleading, erroneous, or incomplete– Insufficient information to assess risks to subjects– Exclusion by gender for life-threatening disease


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• Grounds for imposing a clinical hold for phase 2/3 trials: [21 CFR 312.42(b)(2)]

– All the reasons listed for phase 1 trials– The protocol is deficient in design to meet its stated

objectives


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• If a deficiency is identified that may be grounds for imposing a clinical hold:

– The review division will attempt to discuss and satisfactorily resolve the matter with you first

– Many potential holds can be resolved through such discussion (e.g., inadequate patient monitoring)


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• If a clinical hold is imposed:

– The review division will notify you by telephone and briefly discuss the clinical hold issues

– A letter will follow detailing the hold issues and what you must do to resolve them


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• Your response to the clinical hold letter:

– Should be complete (i.e., address all the deficiencies identified in the letter)

– If complete, you will receive an acknowledgement letter

– If not complete, RPM will notify you


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• Review division will respond within 30 days of receipt of your response by either:– Removing the clinical hold;– Continuing the clinical hold; or– Modifying the clinical hold (e.g., full to partial)

• If review team cannot meet the 30-day deadline:– Review division will call you and discuss review

progress/what is being done to facilitate completion of the review


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Sponsor Responsibilities

• General responsibilities [21 CFR 312.50]

– Select qualified investigators– Provide investigators with pertinent information– Ensure proper monitoring– Ensure that the investigation is conducted according

to the general investigational plan/protocol– Inform FDA and investigators of significant new

adverse effects/risks


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Sponsor Responsibilities (cont.)• Selecting investigators and monitors [21 CFR 312.53]

– Select investigators that are qualified by training and experience

• Obtain statement of qualifications (CV) from investigators

• Should not use disqualified/debarred individuals (Debarment list: http://www.fda.gov/ora/compliance.ref/debar/default.htm)

– Obtain additional information from investigators• Signed Form FDA 1572 • Clinical protocol to be conducted• Financial disclosure [21 CFR 54]


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Sponsor Responsibilities (cont.)

• Informing investigators [21 CFR 312.55]

– Provide Investigator’s Brochure• Description of drug formulation• Pharm/tox effects and PK/PD information in animals and

humans• Possible risks and side effects• Precautions/special monitoring

– Provide new information regarding adverse events and safe use


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• Review of ongoing investigations [21 CFR 312.56]

– Monitor the progress of all investigations – Review and evaluate evidence of safety and effectiveness of the

investigational drug – Submit reports to FDA re: safety and progress– Assure compliance of investigators– Discontinue investigation if drug presents an unreasonable and

significant risk (notify FDA, IRB, investigators)


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• Recordkeeping and record retention [21 CFR 312.57]

– Receipt, shipment, and disposition of the investigational drug

– Financial interest paid to investigators – Retain records for two years after drug approved OR

investigations are discontinued


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• Permit FDA inspection of records and reports [21 CFR 312.58]– Permit inspection of records and reports related to the

clinical investigations upon request– Provide copies of records and reports upon written

request

• Disposition of unused drug [21 CFR 312.59]– Assure return of all unused supplies of the

investigational drug– Ensure safe disposition (does not expose humans to

risks)


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Transfer of Responsibilities

• You may transfer any or all of your responsibilities to a contract research organization (CRO) [21 CFR 312.52]

– Inform FDA in writing specifying which responsibilities are being transferred

– CRO must comply with all applicable regulations associated with the transferred responsibilities


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Investigator Responsibilities• General responsibilities [21 CFR 312.60]

– Ensure that the investigation is conducted according to the protocol and applicable regulations

– Protect the rights, safety, and welfare of subjects

• Control of the investigational drug [21 CFR 312.61]

– Administer drug only to subjects– Do not supply the drug to anyone not authorized to

receive it


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Investigator Responsibilities (cont.)

• Recordkeeping and record retention [21 CFR 312.62]

– Case histories [e.g., Case Report Forms (CRFs) and supporting data, signed and dated consent forms, medical records]

– Disposition of the investigational drug (i.e. dates, quantity, and use by subjects)

– Retain records for 2 years after drug is approved for the indication being investigated or 2 years after the investigation is discontinued


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• Investigator reports to the sponsor [21 CFR 312.64]– Progress reports– Safety reports– Final report– Financial disclosure reports

• Assurance of IRB review [21 CFR 312.66]– Assure that an IRB is responsible for review and approval of the

protocol– Report any unanticipated problems involving risk to subjects– Not make any protocol changes without IRB approval except to

eliminate immediate hazards to subjects


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• Permitting FDA inspection of records and reports [21 CFR 312.68]

• Handling of controlled substances [21 CFR 312.69]

– Securely locked; limited access


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IND Amendments

• Protocol amendments [21 CFR 312.30]

• Information amendments [21 CFR 312.31]


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Protocol Amendments

• New Protocol [21 CFR 312.30(a)]

• Changes in Protocol [21 CFR 312.30(b)]

• New Investigator [21 CFR 312.30(c)]


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New Protocol [21 CFR 312.30(a)]

• New study may begin provided:– Submitted to IND– Approved by IRB

• Content and format– Copy of the protocol– Significant differences from previous protocols– Prominent identification (cover letter; form 1571)– Reference to any relevant information in IND– Request for comment (optional)


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Changes in Protocol [21 CFR 312.30(b)]

• Amendment required for:

– Phase 1: Change significantly affecting subject safety

– Phase 2/3: Changes significantly affecting safety, scope, scientific quality


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Changes in Protocol (cont.)

• Protocol changes may be implemented provided:– Change submitted to IND– Approved by IRB

• Exception: Change to eliminate an apparent immediate hazard to subjects can be implemented immediately.


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Changes in Protocol (cont.)

• Content and Format– Description of the change– Reference to original protocol submission– Prominent identification (cover letter; form

1571)– Reference to any relevant information in IND– Request for comment (optional)


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New Investigator [21 CFR 312.30(c)]

• An amendment is required when a new investigator is added to an ongoing study – Exception: adding a licensed practitioner to a

treatment IND/treatment protocol

• Submit within 30 days of the new investigator being added

• Grouping several new investigators in one submission is permitted


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New Investigator (cont.)

• Content and Format– Name and qualifications– Reference to previously submitted protocol– Prominent identification (cover letter; form

1571)– Additional info required under 21 CFR

312.23(a)(6)(iii)(b)


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Information Amendments [21 CFR 312.31]

• Amendment required for submission of essential information not within scope of protocol amendment, safety report, annual report– New information (e.g., clinical, clinical

pharmacology, nonclinical; chemistry, study reports)

– Discontinuance of study (within 5 days of decision)


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Information Amendments (cont.)

• Submit as necessary (but to the extent possible, no more than every 30 days)

• Content and Format– Prominent identification (cover letter; form

1571)– Statement of nature and purpose– Organized in format appropriate for scientific

review– Request for comment (optional)


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IND Reporting Requirements

• Safety Reports [21 CFR 312.32]

• Annual Reports [21 CFR 312.33]


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Safety Reports: Definitions [21 CFR 312.32(a)]

• Associated with the use of the drug: reasonable possibility of causality

• Disability: substantial disruption of ability to conduct normal life functions

• Life-threatening adverse drug experience (ADE): immediate risk of death (based on investigator’s judgment)

• Serious ADE: any dose resulting in death; life-threatening ADE; hospitalization/prolonged hospitalization; disability; congenital anomaly/birth defect; medical event requiring medical/surgical intervention

• Unexpected ADE: specificity/severity inconsistent with known safety profile


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Review of Safety Information [21 CFR 312.32(b)]

• Review all information relevant to the safety of the drug from all sources (foreign and domestic) including:– Clinical, epidemiological, and animal

investigations– Commercial marketing experience– Scientific literature reports– Unpublished scientific papers– Reports from foreign regulatory authorities


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Types of Safety Reports

• Written 15-day reports• Telephone/fax 7-day reports• Follow-up reports


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Written Safety Reports [21 CFR 312.32(c)(1)]

• Notify FDA in writing of:– Any ADE associated with the use of the drug

that is both serious and unexpected– Any finding from tests in lab animals that

suggests significant risks for human subjects• When?

– ASAP; NO LATER THAN 15 days after receipt of information


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Written Safety Reports (cont.)

• Content and Format– FDA Form 3500A (MedWatch) or narrative

format identified as “IND Safety Report”– Reference previous, similar reports– Analyze the significance of the ADE in light of

similar adverse events


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Telephone/Fax Safety Reports [21 CFR 312.32(c)(2)]

• Notify FDA by telephone or fax of:– Any unexpected fatal or life-threatening

ADE associated with the use of the drug• When?

– ASAP; NO LATER THAN 7 days after sponsor’s receipt of information


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Follow-up Safety Reports [21 CFR 312.32(d)]

• Submit all relevant follow-up info ASAP

• Missed reports (not initially determined to be reportable): Submit ASAP but NO LATER THAN 15 days from discovery


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Safety Reports: Miscellaneous• Variations [21 CFR 312.32(c)(3)]

– FDA may request varying frequency and format: Sponsor/FDA agreement

• Results of investigation of other safety information that does not fall under the specific reporting categories are submitted via:– Information amendment– Annual Report

• Disclaimer [21 CFR 312.32(e)]: You need not admit, and may deny, that the safety report constitutes an admission that the drug caused or contributed to the ADE


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Annual Report [21 CFR 312.33]

Report of the progress of the investigation that includes:

• Individual study information– Title, purpose, patient population, study status– Total # of subjects planned, #entered to date,

by age group, gender, and race; the #completed as planned, #drop-outs

– Study results, if completed


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Annual Report (cont.)• Summary Information

– Most frequent and most serious ADEs by body system

– Summary of all IND safety reports submitted during past year

– Study drop-outs due to ADEs– Subjects who died during study; cause of death– New info re drug’s actions– Completed nonclinical studies; summary of major

findings– CMC changes


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Annual Report (cont.)

• General investigational plan for coming year• Revisions to the Investigator Brochure• Phase 1 study modifications not previously

reported• Significant foreign marketing developments• Log of outstanding business (optional)


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Annual Report (cont.)

• Must be submitted within 60 days of the “in effect” anniversary date

• May request bundled annual reports/waiver of anniversary date

• Multiple applications for the same active moiety• Harmonize and consolidate annual report


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Inactivation [21 CFR 312.45]

• You or FDA may initiate inactivation if:– No subjects entered into studies for >2 years– All investigations on clinical hold for >1 year

• If FDA initiates inactivation:– Pre-inactivation letter issued to you– You have 30 days to respond


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Inactivation (cont.)

• If IND inactivated:

– All investigators notified– Stocks of drug returned to you or disposed of

properly– Annual reports need not be submitted


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Reactivation [21 CFR 312.45(d)]

• If you intend to resume clinical investigations under an inactive IND, you must submit a protocol amendment that includes:– Proposed general investigational plan– Appropriate protocol(s)– Additional information supporting the protocol(s)– Reference previously submitted information

• Safety review– The review division will determine whether your reactivated IND

is safe to proceed or will be placed on clinical hold within 30 days of receipt of your protocol amendment


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Withdrawal [21 CFR 312.38]

• You may withdraw an IND at any time – Notify FDA– All investigations end– All current investigators notified– All stocks of the drug returned to you

• If IND is withdrawn due to safety reasons:– All of the above plus:

• Notify reviewing IRBs• Reasons for the withdrawal


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Termination [21 CFR 312.44]

• FDA may terminate an IND based on:– Deficiencies in the IND– Conduct of an investigation – An IND that remains on inactive status for >5 years

(21 CFR 312.45)

• Pre-termination letter issued: allows you 30 days to respond to our proposal to terminate except where there is immediate and substantial danger to health of individuals


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Questions?• Email: [email protected]• Phone: 301-796-1017• Mailing Address:

10903 New Hampshire Ave.Building 22, Room 5208Silver Spring, MD 20993-0002

Documents

Submitting an IND: What You Need to Know